Continuous release of endostatin from microencapsulated engineered cells for tumor therapy

ABSTRACT Research studies suggest that tumor-related angiogenesis contributes to the phenotype of malignant gliomas. We assessed the effect of local delivery of the angiogenesis inhibitor

endostatin on human glioma cell line (U-87MG) xenografts. Baby hamster kidney (BHK) cells were stably transfected with a human endostatin (hES) expression vector and were encapsulated in

alginate-poly L-lysine (PLL) microcapsules for long-term delivery of hES. The release of biologically active endostatin was confirmed using assays of bovine capillary endothelial (BCE)

proliferation and of tube formation. Human endostatin released from the microcapsules brought about a 67.2% inhibition of BCE proliferation. Furthermore, secreted hES was able to inhibit

tube formation in KDR/PAE cells (porcine aortic endothelial cells stably transfected with KDR, a tyrosine kinase) treated with conditioned U-87MG medium. A single local injection of

encapsulated endostatin-secreting cells in a nude mouse model resulted in a 72.3% reduction in subcutaneous U87 xenografts' weight 21 days post treatment. This inhibition was achieved

by only 150.8 ng/ml human endostatin secreted from 2 × 105 encapsulated cells. Encapsulated endostatin-secreting cells are effective for the treatment of human glioblastoma xenografts.

Continuous local delivery of endostatin may offer an effective therapeutic approach to the treatment of a variety of tumor types. Access through your institution Buy or subscribe This is a

preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online access $209.00 per

year only $17.42 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated

during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS SELF-ASSEMBLED

DODECYL GROUP-MODIFIED GELATIN MICROPARTICLE-BASED HYDROGELS WITH ANGIOGENIC PROPERTIES Article Open access 06 July 2020 A VASCULARIZED TUMOROID MODEL FOR HUMAN GLIOBLASTOMA ANGIOGENESIS

Article Open access 01 October 2021 A THERAPEUTIC VASCULAR CONDUIT TO SUPPORT IN VIVO CELL-SECRETED THERAPY Article Open access 29 July 2021 REFERENCES * Black, P.M. Brain tumor. Part 2. _N.

Engl. J. Med._ 324, 1555–1564 (1991). Article  CAS  Google Scholar  * Leon, S.P., Folkerth, R.D. & Black, P.M. Microvessel density is a prognostic indicator for patients with astroglial

brain tumors. _Cancer_ 77, 362–372 (1996). Article  CAS  Google Scholar  * Folkman, J. Angiogenesis inhibitors generated by tumors. _Mol. Med._ 1, 120–122 (1995). Article  CAS  Google

Scholar  * Hanahan, D. & Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. _Cell _ 86, 353–364 ( 1996). Article  CAS  Google Scholar  * Kerbel,

R.S. A cancer therapy resistant to resistance. _Nature_ 390 , 335–336 (1997). Article  CAS  Google Scholar  * Hanahan, D. A flanking attack on cancer. _Nat. Med._ 4, 13–14 (1998). Article 

CAS  Google Scholar  * Brem, S., Brem, H., Folkman, J., Finkelstein, D. & Patz, A. Prolonged tumor dormancy by prevention of neovascularization in the vitreous. _Cancer Res._ 36,

2807–2812 (1976). CAS  PubMed  Google Scholar  * Holmgren, L., O'Reilly, M.S. & Folkman, J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of

angiogenesis suppression. _Nat. Med._ 1, 149–153 ( 1995). Article  CAS  Google Scholar  * Tanaka, T., Manome, Y., Wen, P., Kufe, D.W. & Fine, H.A. Viral vector-mediated transduction of a

modified platelet factor 4 cDNA inhibits angiogenesis and tumor growth. _Nat. Med. _ 3, 437–442 ( 1997). Article  CAS  Google Scholar  * Takamiya, Y., Brem, H., Ojeifo, J., Mineta, T. &

Martuza, R.L. AGM-1470 inhibits the growth of human glioblastoma cells in vitro and in vivo. _Neurosurgery_ 34, 869–875 (1994). CAS  PubMed  Google Scholar  * Takamiya, Y., Friedlander,

R.M., Brem, H., Malick, A. & Martuza, R.L. Inhibition of angiogenesis and growth of human nerve-sheath tumors by AGM-1470. _J. Neurosurg. _ 78, 470–476 ( 1993). Article  CAS  Google

Scholar  * Lee, J.K., Choi, B., Sobel, R.A., Chiocca, E.A. & Martuza, R.L. Inhibition of growth and angiogenesis of human neurofibrosarcoma by heparin and hydrocortisone. _J Neurosurg. _

73, 429–435 ( 1990). Article  CAS  Google Scholar  * Tamargo, R.J., Leong, K.W. & Brem, H. Growth inhibition of the 9L glioma using polymers to release heparin and cortisone acetate. _J

Neurooncol. _ 9, 131–138 ( 1990). Article  CAS  Google Scholar  * O'Reilly, M.S. _ et al_. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a

Lewis lung carcinoma. _Cell_ 79, 315–328 (1994). Article  CAS  Google Scholar  * Kirsch, M. _ et al_. Angiostatin suppresses malignant glioma growth in vivo. _ Cancer Res._ 58, 4654–4659

(1998). CAS  PubMed  Google Scholar  * O'Reilly, M.S. _ et al_. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. _Cell_ 88, 277–285 (1997). Article  CAS  Google

Scholar  * Lim, F. & Sun, A.M. Microencapsulated islets as bioartificial endocrine pancreas. _Science_ 210, 908– 910 (1980). Article  CAS  Google Scholar  * Soon-Shiong, P. _ et al_.

Insulin independence in a type 1 diabetic patient after encapsulated islets transplantation. _Lancet_ 143, 950– 955 (1994). Article  Google Scholar  * Lanza, R.P., Hayes, J.L. & Chick,

W.L. Encapsulated cell technology. _Nat. Biotechnol. _ 14, 1107–1111 ( 1996). Article  CAS  Google Scholar  * Ismail, N., Hortelano, G. & Al-Hendy, A. Growth hormone gene therapy using

Encapsulated myoblast . In _Cell encapsulation technology and therapeutics_. (eds Kuhetreiber, W.M., Lanza, R.P. & Chick, W.L.) 343– 350 (Birkhauser, Boston, MA; 1999). Chapter  Google

Scholar  * Machluf, M., Orsola, A. & Atala, A. Controlled release of therapeutic agents: slow delivery and cell encapsulation. _World J. Urol._ 18, 80–83 (2000). Article  CAS  Google

Scholar  * Savelkoul, H.F.J. _ et al_. Modulation of systemic cytokine levels by implantation of alginate-encapsulated cells. _J. Immunol. Methods_ 170 , 185–196 (1994). Article  CAS  Google

Scholar  * Machluf, M., Regev, O., Peled, Y., Kost, J. & Cohen, S. Characterization of microencapsulated liposome systems for the controlled delivery of liposome-associated

macromolecules. _ J. Contr. Release_ 43, 35–45 (1996). Article  Google Scholar  * Prakash, S. & Chang, T.M.S. Microencapsulated genetically engineered live _E. coli_ DH5 cells

administered orally to maintain normal plasma urea level in uremic rats. _Nat. Med._ 2, 883–887 (1996). Article  CAS  Google Scholar  * Gasper, L.E. _ et al_. Supratentorial malignant

glioma: patterns of recurrence and implications for external beam local treatment. _Int. J. Radiat. Oncol. Biol. Phys._ 24, 55–57 (1992). Article  Google Scholar  * Liang, B.C., Thornton,

A.F. Jr., Sandler, H.M. & Greenberg, H.S. Malignant astrocytomas: focal tumor recurrence after focal external beam radiation therapy. _J. Neurosurg._ 75, 559–563 (1991). Article  CAS 

Google Scholar  * Sneed, P.K. _ et al_. Patterns of recurrence of glioblastoma multiforme after external irradiation followed by implant boost. _Int. J. Radiat. Oncol. Biol. Phys._ 29,

719–727 ( 1994). Article  CAS  Google Scholar  * O'Reilly, M.S., Holmgren, L., Chen, C. & Folkman, J. Angiostatin induces and sustains dormancy of human primary tumors in mice .

_Nat. Med._ 2, 689–692 (1996). Article  CAS  Google Scholar  * Boehm, T., Folkman, J., Browder, T. & O'Reilly, M.S. Antiangiogenic therapy of experimental cancer does not induce

acquired drug resistance. _Nature_ 390, 404– 407 (1997). Article  CAS  Google Scholar  * Fenstermacher, J.D., Blasberg, R.G. & Patlak, C.S. Methods for quantifying the transport of drugs

across brain barrier systems. _Pharmacol. Ther._ 14, 217–248 (1981). Article  CAS  Google Scholar  * Jain, R.K. Haemodynamic and transport barriers to the treatment of solid tumours. _ Int.

J. Radiat. Biol._ 60, 85–100 (1991). Article  CAS  Google Scholar  * Yamaguchi, N. _ et al_. Endostatin inhibits VEGF-induced endothelial cell migration and tumor growth independently of

zinc binding. _EMBO J._ 18, 4414–4423 (1999). Article  CAS  Google Scholar  * Blezinger, P. _ et al_. Systemic inhibition of tumor growth and tumor metastases by intramuscular administration

of the endostatin gene. _Nat. Biotechnol. _ 17, 343–348 ( 1999). Article  CAS  Google Scholar  * Chartier, C., Degryse, M., Dieterle, A., Pavirani, A. & Mehtali, M. Efficient generation

of recombinant adenovirus vectors by homologous recombination in _Escherichia coli_. _ J. Virol._ 113, 178–183 ( 1991). Google Scholar  * Deroanne, C.F., Hajitou, A., Calberg-Bacq, C.M.,

Nusgens, B.V. & Lapiere, C.M. Angiogenesis by fibroblast growth factor 4 is mediated through an autocrine up-regulation of vascular endothelial growth factor expression. _Cancer Res._

57, 5590–5597 (1997). CAS  PubMed  Google Scholar  * Waltenberger, J., Claesson-Welsh, L., Siegbahn, A., Shibuya, M. & Heldin, C.H. Different signal transduction properties of KDR and

Flt1, two receptors for vascular endothelial growth factor. _J. Biol. Chem._ 269, 26988 –26995 (1994). CAS  PubMed  Google Scholar  * Carroll, R.S. _ et al_. KDR activation in astrocytic

neoplasms. _Cancer. _ 7, 1335–1341 ( 1999). Article  Google Scholar  * Weidner, N., Semple, J.P., Welch, W.R. & Folkman, J. Tumor angiogenesis and metastasis—correlation in invasive

breast carcinoma . _N. Engl. J. Med._ 324, 1– 8 (1991). Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We wish to thank Dr. Judah Folkman for his helpful suggestions in

the preparation of the manuscript. This work is supported by a grant from the Boston Neurosurgical Foundation. T.J. is a recipient of a fellowship from Jikei University School of Medicine.

AUTHOR INFORMATION Author notes * Tatsuhiro Joki and Marcelle Machluf: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Department of Neurosurgery Department of

Surgery, Brain Tumor Laboratory, Brigham Women's Hospital, Harvard Medical School, Boston, 02115, MA Tatsuhiro Joki, Jianhong Zhu, Nicholas T. Seyfried, Ian F. Dunn, Rona S. Carroll 

& Peter McL. Black * Children's Hospital, Harvard Medical School, Boston, 02115, MA Tatsuhiro Joki, Jianhong Zhu, Nicholas T. Seyfried, Ian F. Dunn, Rona S. Carroll & Peter McL.

Black * Department of Neurosurgery, Jikei University School of Medicine, Tokyo, Japan Tatsuhiro Joki & Toshiaki Abe * Department of Urology, The Children's Hospital, Harvard

Medical School, Boston, 02115, MA Marcelle Machluf & Anthony Atala Authors * Tatsuhiro Joki View author publications You can also search for this author inPubMed Google Scholar *

Marcelle Machluf View author publications You can also search for this author inPubMed Google Scholar * Anthony Atala View author publications You can also search for this author inPubMed 

Google Scholar * Jianhong Zhu View author publications You can also search for this author inPubMed Google Scholar * Nicholas T. Seyfried View author publications You can also search for

this author inPubMed Google Scholar * Ian F. Dunn View author publications You can also search for this author inPubMed Google Scholar * Toshiaki Abe View author publications You can also

search for this author inPubMed Google Scholar * Rona S. Carroll View author publications You can also search for this author inPubMed Google Scholar * Peter McL. Black View author

publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Rona S. Carroll. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS

ARTICLE CITE THIS ARTICLE Joki, T., Machluf, M., Atala, A. _et al._ Continuous release of endostatin from microencapsulated engineered cells for tumor therapy. _Nat Biotechnol_ 19, 35–39

(2001). https://doi.org/10.1038/83481 Download citation * Received: 24 May 2000 * Accepted: 18 September 2000 * Issue Date: January 2001 * DOI: https://doi.org/10.1038/83481 SHARE THIS

ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard

Provided by the Springer Nature SharedIt content-sharing initiative